Withdrawal from acute alcohol exposure produces profound changes in behavior including reduced exploration and locomotor activity as well as suppressed social interaction. These behavioral changes characterize the "hangover" state and are remarkably similar to sickness behaviors that are typically observed during acute illness produced by infectious agents or injection of pro-inflammatory cytokines. We therefore propose that behavioral responses during withdrawal from acute alcohol exposure in rats may be viewed as sickness-like behavioral responses that are initiated and maintained by activation of inflammatory-related pathways traditionally associated with immune activation. Our preliminary data indicate robust increases in transcriptional activity of interleukin-1 in CNS sites that are crucial for normal progression of the immune response and the generation of sickness behaviors. The goal of the following proposal, therefore, is to (Aim 1) establish the temporal and spatial characteristics of cytokine responses produced by hangover, (Aim 2) to identify probable cellular and neurochemical mechanisms of cytokine responses produced by hangover, and (Aim 3) to forge a positive mechanistic link between increased central cytokines and the sickness-like behavioral changes observed during hangover in rats.